Disease relevance of Methylation

• The methyl-accepting chemotaxis proteins of E. coli: a repellent-stimulated, covalent modification, distinct from methylation [1].
• The role of the primary mammalian DNA methyltransferase, DNMT1, in maintaining CpG island methylation in human colon cancer cells has recently been questioned [2].
• We examined gliomas to determine whether methylation of the MGMT promoter is related to the responsiveness of the tumor to alkylating agents [3].
• Partially deficient methylation of cytosine in DNA at CCATGG sites stimulates genetic recombination of bacteriophage lambda [4].
• Fragile X syndrome is associated with massive expansion of a CGG trinucleotide repeat within the FMR-1 gene and transcriptional silencing of the gene due to abnormal methylation [5].

Psychiatry related information on Methylation

• DNA cytosine methylation in brain of patients with Alzheimer's disease [6].
• FANCF methylation was associated with a shorter duration of tobacco use (P=0.03) and a younger age of starting smoking (P=0.06) in NSCLC, and with a greater number of years of alcohol drinking (P=0.02) in HNSCC [7].
• Mutations in the human ATRX gene result in X-linked alpha-thalassaemia with mental retardation (ATRX) syndrome and correlate with changes in methylation of repetitive DNA sequences [8].
• Recent data suggest that class prediction models, based on defined molecular profiles, and assessment of MGMT promoter methylation might contribute to improved patient stratification and decision making [9].
• The finding of reduced methylation at the G6 PD promoter is an interesting finding and suggests that there could be widespread dysregulation of X chromosomal genes in Rett syndrome [10].

High impact information on Methylation

• Large-genome eukaryotes use heritable cytosine methylation to silence promoters, especially those associated with transposons and imprinted genes [11].
• Two methyltransferases from archaebacteria that catalyze methylation of mercaptoethanesulfonate (coenzyme M) during methanogenesis have also been shown to contain histidine-ligated cobamides [12].
• Thymidylate synthase (TS, EC 2.1.1.45) catalyzes the reductive methylation of dUMP by CH2H4folate to produce dTMP and H2folate [13].
• Carnitine biosynthesis is initiated by methylation of lysine [14].
• We show that a paternally derived targeted deletion of the germline differentially methylated region (DMR) associated with the antisense Nespas transcript unexpectedly affects both the expression of all transcripts in the cluster and methylation of two DMRs [15].

Chemical compound and disease context of Methylation

• Loss of Apaf-1 expression is accompanied by allelic loss in metastatic melanomas, but can be recovered in melanoma cell lines by treatment with the methylation inhibitor 5-aza-2'-deoxycytidine (5aza2dC) [16].
• These findings, besides increasing the proportion of caucasian individuals whose haemophilia B carrier state can be diagnosed from 79% to 89%, demonstrate this widely applicable use of PCR for the detection of DNA polymorphism at cytosine phosphoguanadine dinucleotides irrespective of the methylation status [17].
• There were no correlations between SAM or SAH concentrations or methylation ratio and age or sex in both groups, or serum B12 and folate concentrations, CSF folate, serum or CSF methylmalonic acid, risk factors, body mass index, specific drug treatment received, or disease stage in the HIV group [18].
• To determine the sequence elements that confer auxin inducibility to the GH3 promoter, we used gel mobility shift assays, methylation interference, deletion analysis, linker scanning, site-directed mutagenesis, and gain-of-function analysis with a minimal cauliflower mosaic virus 35S promoter [19].
• We propose that IOMT colocalizes with the endoplasmic reticulum-associated isoflavone synthase cytochrome P450 to ensure rapid B-ring methylation of the unstable 2,4',7-trihydroxyisoflavanone product of isoflavone synthase, thereby preventing its dehydration to daidzein and subsequent A-ring methylation by free IOMT [20].

Biological context of Methylation

• Cytosine methylation does not reinforce or replace ancestral gene regulation pathways but instead endows methylated genomes with the ability to repress specific promoters in a manner that is buffered against changes in the internal and external environment [11].
• Histone lysine methylation is a key regulator of gene expression and heterochromatin function, but little is known as to how this modification impinges on other chromatin activities [21].
• NoRC mediates rDNA silencing by recruiting DNA methyltransferase and histone deacetylase activity to the rDNA promoter, thus establishing structural characteristics of heterochromatin such as DNA methylation, histone hypoacetylation and methylation of the Lys9 residue of histone H3 [22].
• In Sp1-/- embryos, the expression of many putative target genes, including cell cycle-regulated genes, is not affected, CpG islands remain methylation free, and active chromatin is formed at the globin loci [23].
• These results indicate an activator-based mechanism for joint MLL1 and MOF recruitment and targeted methylation and acetylation and provide a molecular explanation for the closely correlated distribution of H3 K4 methylation and H4 K16 acetylation on active genes [24].

Anatomical context of Methylation

• We now show that the pattern of differential methylation in the 5' portion of H19 is established in the gametes and a subset is maintained in the pre-implantation embryo [25].
• We report that CpG island methylation, an epigenetic modification of DNA known to correlate closely with silencing of gene transcription, appears in the oestrogen receptor (ER) gene in a subpopulation of cells which increases as a direct function of age in human colonic mucosa [26].
• Although genomic methylation patterns were established normally in Dnmt1o-deficient oocytes, embryos derived from such oocytes showed a loss of allele-specific expression and methylation at certain imprinted loci [27].
• Here we show that in the affected individual, in a transgenic model and in differentiating embryonic stem cells, transcription of antisense RNA mediates silencing and methylation of the associated CpG island [28].
• We conclude that methylation at Hpa II sites is replicated by these cultured cells but not with 100% fidelity [29].

Associations of Methylation with chemical compounds

• Recognition of the methyl groups and CG sequence at the methylation site is due to five highly conserved residues that form a hydrophobic patch [30].
• AdoMet-dependent methylation of histones is part of the "histone code" that can profoundly influence gene expression [31].
• Methylation of arginine residues within histone H3 has been linked to active transcription [32].
• Methylenetetrahydrofolate reductase (MTHFR) catalyses the reduction of methylenetetrahydrofolate to methyltetrahydrofolate, a cofactor for homocysteine methylation to methionine [33].
• The effects of a variety of antitubuin and antimicrofilament agents on phosphatidylcholine synthesis via the methylation of phosphatidyl-ethanolamine and its formation through CDP-choline were studied [34].

Gene context of Methylation

• Genetic experiments have defined the importance of the DNA methyltransferase Dnmt1 for the maintenance of methylation in mouse cells and its role in neoplasia [35].
• In this system, Dnmt3a functioned as a de novo methyltransferase, whereas Dnmt1 had no detectable de novo methylation activity [36].
• CTCF maintains differential methylation at the Igf2/H19 locus [37].
• When co-expressed, Dnmt1 and Dnmt3a cooperated to establish and maintain methylation patterns [36].
• Here we demonstrate arginine methylation of STAT1 by the protein arginine methyl-transferase PRMT1 as a novel requirement for IFNalpha/beta-induced transcription [38].

Analytical, diagnostic and therapeutic context of Methylation

• The methylation status of the BssHII site at the CpG island was also studied by Southern blot analysis of DNA from patients, carriers, and controls [39].
• Experiments with the restriction enzyme Hpa II, which is sensitive to cytosine methylation in the sequence CCGG, demonstrated that the DNA synthesized in 5-aza-CR-treated cultures was maximally undermethylated 48 hr after treatment [40].
• Chromatin immunoprecipitation indicates that epigenetic activation of Ultrabithorax transcription in Drosophila coincides with trivalent methylation by Ash1 and recruitment of Brm [41].
• Chromatin immunoprecipitations show that Rb is necessary to direct methylation of histone H3, and is necessary for binding of HP1 to the cyclin E promoter [42].
• The first factor has been found indistinguishable from NF-kappa B by mobility shift assays, methylation interference, competition binding studies, and supershift analysis using an antiserum specific for the p50 component [43].

References